The Weak-Link Approach (WLA) is a supramolecular coordination-based assembly methodology, first introduced in 1998 by the Mirkin Group at Northwestern University. [1] This method takes advantage of hemilabile ligands -ligands that contain both strong and weak binding moieties- that can coordinate to metal centers and quantitatively assemble into a single condensed ‘closed’ structure (Figure 1). Unlike other supramolecular assembly methods, the WLA allows for the synthesis of supramolecular complexes that can be modulated from rigid ‘closed’ structures to flexible ‘open’ structures through reversible binding of allosteric effectors at the structural metal centers. The approach is general and has been applied to a variety of metal centers and ligand designs including those with utility in catalysis and allosteric regulation.
There are three main components of the WLA methodology that enable the in situ control of supramolecular architecture: 1) the utilization of hemilabile ligands, 2) the choice of metal centers, and 3) the type of allosteric effector.
A key component of the WLA is the use of hemilabile ligands. [2] [3] Hemilabile ligands are polydentate chelates that contain at least two different types of bonding groups, denoted X and Y (Figure 2). The first group (X) bonds strongly to the metal center, while the other group (Y) is weakly bonding and easily displaced by coordinating ligands or solvent molecules (Z). In this way, the substitutionally labile group (Y) can be displaced from the metal center yet remain available for recoordination. For WLA-generated structures, a typical ligand design consists of a phosphine-based strong binding group and a weak-binding group containing O, S, Se, or N. More recent reports have utilized N-heterocyclic carbenes (NHC) as the strong-binding moiety. By using a combination of NHC- and phosphine-based hemilabile ligands, heteroligated complexes, [4] and macrocycles [5] have been successfully synthesized, allowing access to more complex architectures with sophisticated functions.
Due to the well-developed understanding of the reactions between the hemilabile ligands and d8 metal ions, the WLA has relied extensively on this type of metal center within its methodology. Initial reports focused on the use of Rh(I), [1] but Ir(I), [6] Ni(II), [7] Pd(II), [8] and Pt(II) [9] have all been successfully employed. While d8 metal centers dominate the WLA literature, d6 Ru(II) [10] and d9 Cu(I) [11] have also been utilized. Importantly, the choice of metal centers tunes the identity and selectivity of the various allosteric effectors.
The use of hemilabile ligands allows structural motifs synthesized via the WLA to be modified with small molecule effectors much like allosteric enzymes in biology. As described above, the weak Y–M bond can be easily displaced by a coordinating ligands including Cl−, CO, CH3CN, RCO2−, and a variety of nitriles/isonitriles (Figure 2). Typical WLA constructs rely on the allosteric effector’s stronger affinity for the metal center versus the weakly binding Y moiety. Upon introduction of these effectors, the closed, rigid structures open to their more flexible form. The closed structures can then be reformed in situ by halide abstraction agents, such as noncoordinating silver and thallium salts, or by evacuation of the reaction chamber to remove solvent or small molecules. Recent progress has shown that the inclusion of pendent redox active transition metal groups in the WLA ligands enables control over the binding of ancillary ligands to a redox-inactive Pt(II) center via oxidation and reduction of the distal metal site (Figure 3). [12] This discovery highlights that new forms of stimuli can be incorporated into the WLA for the design of novel stimuli-responsive materials.
The generality of the WLA and its ability to accommodate a multitude of functional groups has allowed the facile synthesis of both molecular and supramolecular architectures. These structures can be broadly grouped into two classes of compounds based on the coordination geometry of the “closed” complexes: 1) cis-WLA complexes and 2) trans-WLA complexes.
The majority of WLA architectures synthesized to date can be classified as cis-WLA complexes. The strong-binding moieties adopt cis-coordination geometry around the metal center in these complexes, regardless of the identities of the strong-binder. For example, the heteroligated complex shown in Figure 3 is understood to be a cis-WLA complex because both the NHC- and phosphino- groups, the strong-binding components, are cis relative to each other. Using these complexes, molecular tweezers, macrocycles, and triple-layer structures have all been successfully synthesized (Figure 4). In 2017, the Mirkin group reported infinite coordination polymer particles incorporating WLA approach complexes. [13] The extended structure was successfully obtained by appending secondary terpyridine groups onto the hemilabile ligands within the WLA subunits and allowing them to selectively bind Fe(II) ions (Figure 5).
The first trans-WLA complex was reported by the Mirkin group in 2017. [14] In this complex, two NHC groups adopt a trans-coordination geometry around a Pd(II) metal center due to the addition of the sterically bulky tert-butyl groups to the imidazole ring of the hemilabile ligand. Upon effector binding, a linear change of up to ~9Å was observed (Figure 6). To date, only this molecular complex has been reported utilizing a trans-WLA complex.
Allosteric regulation in supramolecular structures generated via the WLA is particularly important in the context of designing and synthesizing novel, bioinspired catalytic systems, where the conformation of the complex controls the activity of the catalyst. Below are a series of different catalytic motifs that have been constructed via the WLA and a discussion of the control mechanisms that can be used to modulate catalytic activity:
The first catalytically active supramolecular structure generated via the WLA was designed to operate via a mechanism inspired by the Enzyme Linked ImmunoSorbent Assay (ELISA). [16] In such a supramolecular system, a target sandwiching event creates a catalyst target complex that subsequently generates chemiluminescent or fluorescent readout. For example, a homologated WLA-based Rh(I) macrocyclic structure has been developed that incorporates pyridine-bisimine Zn(II) moieties and behaves as an efficient and completely reversible allosteric modulator for the hydrolysis of 2-(hydroxypropyl)-p-nitrophenyl phosphate (HPNP), a model substrate for RNA (Figure 7). [15] Significantly, the structural changes induced by small molecule regulators Cl− and CO transition this system from a catalytically inactive state to a very active one in a highly reversible fashion. Further, this system provides a highly sensitive platform for sensing chloride anions. As chloride binds to the Rh(I) centers, the complex is opened, allowing hydrolysis to occur. The hydrolysis product of the reaction (p-nitrophenolate) can be followed by UV-vis spectroscopy. As in ELISA, the WLA-generated mimic can take a small amount of target (chloride anions) and produce a large fluorescent readout that can be utilized for detection.
There are several notable conclusions that can be drawn based on the catalytic studies of this complex. The first is that the closed complex is completely inactive under hydrolysis conditions. Second, the open complex is extremely active and capable of quantitatively hydrolyzing all the HPNP substrate in less than 40 min. By simply bubbling N2 into the solution, the reformation of the closed complex and the generation of an inactive catalyst can be achieved.
The polymerase chain reaction (PCR) is utilized in biochemistry and molecular biology for exponentially amplifying nucleic acids by making copies of a specific region of a nucleic acid target. When coupled with diagnostic probes, this technique allows one to detect a small collection of molecules under very dilute conditions. A limitation of PCR is that it only works with nucleic acid targets, and there are no known analogues of PCR for other target molecular candidates.
Using the WLA, this type of target amplification approach has been exemplified in an abiotic system. By incorporating Zn(II)-salen ligands into a supramolecular assembly, an acyl transfer reaction involving acetic anhydride and pyridylcarbinol as substrates was investigated. [17] In the absence of acetate, there is almost no catalytic activity. Once a small amount of tetrabutylammonium acetate reacts with inactive complex at its two rhodium centers that serve as structural regulatory sites, it is converted into open cavity complex, which then catalyzes the reaction (Figure 8).
In the early stages of the reaction, only a minor amount of the catalyst is activated. As the reaction proceeds, more acetate is generated, which leads to the formation of more activated complex and progressively faster catalysis. This type of behavior is typical for cascade reactions including PCR. Unlike the previous example in which the catalyst produced a signal amplifier, this catalyst is a target amplifier making more copies of the target acetate. Following the reaction by gas chromatography, one observes that the generation of products follows a sigmoidal curve, indicative of a PCR-like cascade reaction system.
There was also a need to design a catalytic structure that would allow for the inclusion of mono-metallic catalyst that could be completely turned off. To this end the triple-layer motif was developed, composed of two transition metal nodes, two chemically inert blocking exterior layers, and a single catalytically active interior ligand. This complex was synthesized using the WLA and halide induced ligand rearrangement processes, and it can be reversibly activated and deactivated through small-molecule or elemental anion effector reactions that assemble and disassemble the trilayer structures. In a Al(III)-salen example, the polymerization of ε-caprolactone could be turned on and off based on the ancillary ligands and abstraction agents added to the system (Figure 9). [18] Unlike with previous catalytic structures that utilized bimetallic systems, the tri-layer motif allows for the incorporation of a monometallic catalyst, opening the scope of potential catalysts that can be employed using these types of structures.
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electron pairs, often through Lewis bases. The nature of metal–ligand bonding can range from covalent to ionic. Furthermore, the metal–ligand bond order can range from one to three. Ligands are viewed as Lewis bases, although rare cases are known to involve Lewis acidic "ligands".
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically constitutes the addition of pairs of hydrogen atoms to a molecule, often an alkene. Catalysts are required for the reaction to be usable; non-catalytic hydrogenation takes place only at very high temperatures. Hydrogenation reduces double and triple bonds in hydrocarbons.
Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, electrostatic charge, or hydrogen bonding to strong covalent bonding, provided that the electronic coupling strength remains small relative to the energy parameters of the component. While traditional chemistry concentrates on the covalent bond, supramolecular chemistry examines the weaker and reversible non-covalent interactions between molecules. These forces include hydrogen bonding, metal coordination, hydrophobic forces, van der Waals forces, pi–pi interactions and electrostatic effects.
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Ring-closing metathesis (RCM) is a widely used variation of olefin metathesis in organic chemistry for the synthesis of various unsaturated rings via the intramolecular metathesis of two terminal alkenes, which forms the cycloalkene as the E- or Z- isomers and volatile ethylene.
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A transition metal fullerene complex is a coordination complex wherein fullerene serves as a ligand. Fullerenes are typically spheroidal carbon compounds, the most prevalent being buckminsterfullerene, C60.
In coordination chemistry and catalysis hemilability refers to a property of many polydentate ligands which contain at least two electronically different coordinating groups, such as hard and soft donors. These hybrid or heteroditopic ligands form complexes where one coordinating group is easily displaced from the metal centre while the other group remains firmly bound; a behaviour which has been found to increase the reactivity of catalysts when compared to the use of more traditional ligands.
Supramolecular catalysis is not a well-defined field but it generally refers to an application of supramolecular chemistry, especially molecular recognition and guest binding, toward catalysis. This field was originally inspired by enzymatic system which, unlike classical organic chemistry reactions, utilizes non-covalent interactions such as hydrogen bonding, cation-pi interaction, and hydrophobic forces to dramatically accelerate rate of reaction and/or allow highly selective reactions to occur. Because enzymes are structurally complex and difficult to modify, supramolecular catalysts offer a simpler model for studying factors involved in catalytic efficiency of the enzyme. Another goal that motivates this field is the development of efficient and practical catalysts that may or may not have an enzyme equivalent in nature.
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In homogeneous catalysis, C2-symmetric ligands refer to ligands that lack mirror symmetry but have C2 symmetry. Such ligands are usually bidentate and are valuable in catalysis. The C2 symmetry of ligands limits the number of possible reaction pathways and thereby increases enantioselectivity, relative to asymmetrical analogues. C2-symmetric ligands are a subset of chiral ligands. Chiral ligands, including C2-symmetric ligands, combine with metals or other groups to form chiral catalysts. These catalysts engage in enantioselective chemical synthesis, in which chirality in the catalyst yields chirality in the reaction product.
Bispidine (3,7-diazabicyclo[3.3.1]nonane) is an organic compound that is classified as a bicyclic diamine. Although synthetic, it is related structurally to natural alkaloid sparteine. It is a white crystalline solid. It has been widely investigated as a chelating agent. Many derivatives are known.
Nathan C. Gianneschi is the Jacob & Rosaline Cohn Professor of Chemistry, Materials Science & Engineering, and Biomedical Engineering at Northwestern University and the Associate Director for the International Institute for Nanotechnology. Gianneschi's lab takes an interdisciplinary approach to nanomaterials research, with a focus on multifunctional materials for biomedical applications, programmed interactions with biomolecules and cells, and basic research into nanoscale materials design, synthesis and characterization.
Transition metal porphyrin complexes are a family of coordination complexes of the conjugate base of porphyrins. Iron porphyrin complexes occur widely in Nature, which has stimulated extensive studies on related synthetic complexes. The metal-porphyrin interaction is a strong one such that metalloporphyrins are thermally robust. They are catalysts and exhibit rich optical properties, although these complexes remain mainly of academic interest.